second-generation antipsychotics and neuroleptic malignant

8/18/2019 Second-Generation Antipsychotics and Neuroleptic Malignant

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S Y S T E M A T I C R E V I E W

Second-Generation Antipsychotics and Neuroleptic MalignantSyndrome: Systematic Review and Case Report Analysis

Martino Belvederi Murri • Argentina Guaglianone • Michele Bugliani •

Pietro Calcagno • Matteo Respino • Gianluca Serafini •

Marco Innamorati • Maurizio Pompili • Mario Amore

Published online: 13 January 2015

The Author(s) 2015. This article is published with open access at Springerlink.com

Abstract

Background Neuroleptic malignant syndrome (NMS) is arare, severe, idiosyncratic adverse reaction to antipsychot-

ics. Second-generation antipsychotics (SGAs) were origi-

nally assumed to be free from the risk of causing NMS,

however several cases of NMS induced by SGAs (SGA-

NMS) have been reported.

Objectives The aim of this study was to systematically

review available studies and case reports on SGA-NMS

and compare the presentation of NMS induced by different

SGAs. Data Sources Citations were retrieved from PubMed up

to November 2013, and from reference lists of relevant

citations.

Study Eligibility Criteria Eligibility criteria included

(a) primary studies reporting data on NMS, with at least

50 % of the sample receiving SGAs; or (b) case reports

and case reviews reporting on NMS induced by SGA

monotherapy, excluding those due to antipsychotic

withdrawal.

Study Appraisal and Synthesis Methods A standardized

method for data extraction and coding was developed for

the analysis of eligible case reports.

Results Six primary studies and 186 individual cases

of NMS induced by SGAs were included. Primary

studies suggest that SGA-NMS is characterized by

lower incidence, lower clinical severity, and less fre-

quent lethal outcome than NMS induced by first-gen-

eration antipsychotics. Systematic analysis of case

reports suggests that even the most recently marketed

antipsychotics are not free from the risk of inducing

NMS. Furthermore, clozapine-, aripiprazole- and ami-

sulpride-induced NMS can present with atypical fea-

tures more frequently than other SGA-NMS, i.e.

displaying less intense extrapyramidal symptoms or

high fever.

Limitations Case reports report non-systematic data,

therefore analyses may be subject to bias.

Conclusions and Implications of Key Findings Clinicians

should be aware that NMS is virtually associated with all

antipsychotics, including those most recently marketed.

Although apparently less severe than NMS induced by

older antipsychotics, SGA-NMS still represent a relevant

clinical issue.

Electronic supplementary material The online version of thisarticle (doi:10.1007/s40268-014-0078-0 ) contains supplementarymaterial, which is available to authorized users.

M. Belvederi Murri (&) A. Guaglianone M. Bugliani

P. Calcagno M. Respino G. Serafini M. Amore

Section of Psychiatry, Department of Neuroscience,

Rehabilitation, Ophthalmology, Genetics, Maternal and ChildHealth, University of Genoa, Largo Rosanna Benzi, 10,

16132 Genoa, Italy

e-mail: [email protected]

M. Belvederi Murri

Department of Psychological Medicine, Institute of Psychiatry,

King’s College London, London, UK

M. Innamorati M. Pompili

Department of Neurosciences, Mental Health and Sensory

Organs, Suicide Prevention Center, Sant’Andrea Hospital,

Sapienza University of Rome, Rome, Italy

Drugs R D (2015) 15:45–62

DOI 10.1007/s40268-014-0078-0

http://dx.doi.org/10.1007/s40268-014-0078-0http://dx.doi.org/10.1007/s40268-014-0078-0


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Key Points

Neuroleptic malignant syndrome (NMS) induced by

second-generation antipsychotics is characterized by

lower incidence, lower clinical severity, and less

frequent lethal outcome than NMS induced by first-

generation antipsychotics.

Even the most recently marketed antipsychotics are

not free from the risk of inducing NMS.

Clozapine-, aripiprazole- and amisulpride-induced

NMS can present with atypical features more

frequently than other SGA-NMS, i.e. displaying less

intense extrapyramidal symptoms or high fever.

1 Introduction

Neuroleptic malignant syndrome (NMS) is a rare, unpre-

dictable adverse reaction associated with antipsychotic use.

It is generally characterized by rigidity, tremor, fever,

dysregulated sympathetic nervous system hyperactivity,

alterations of mental status, leukocytosis, and creatine

kinase (CK) elevation [1]. If not promptly recognized and

treated, NMS can lead to patient death or permanent

damages, such as neurological sequelae [2, 3]. Second-

generation antipsychotics (SGAs) were initially assumed to

be free from the risk of inducing NMS because of theirmore favorable pharmacodynamic profile [4]; however,

after they had been marketed, cases of NMS induced by

SGAs (SGA-NMS) began to be reported, with the first case

implicating clozapine [5]. Notably, several cases of NMS

induced by clozapine (CLZ-NMS) presented with different

clinical features than those of NMS induced by first-gen-

eration antipsychotics (FGA-NMS), i.e. lacking cardinal

signs or symptoms. These observations led to the hypoth-

esis that ‘atypical’ antipsychotics might determine ‘atypi-

cal’ forms of NMS on the basis of different

pharmacological properties [6]. Furthermore, newer SGAs

such as aripiprazole [7] and amisulpride [8] possesspeculiar pharmacodynamic profiles [9, 10] which might be

associated with different NMS presentation. At present,

while it is commonly accepted that no antipsychotic is free

from the risk of inducing NMS, there is still uncertainty on

the clinical profile of SGA-NMS [6, 11].

SGAs are the most commonly prescribed antipsychotics

[12] but our knowledge on SGA-NMS continues to be very

limited given the intrinsic difficulties of studying NMS

under experimental conditions. Of note, case reports

remain one of the main sources of information for clini-

cians. Hence, there is still great uncertainty regarding

SGA-NMS epidemiology [13, 14], diagnostic definition

[1], presentation, clinical course, and pathophysiology [15],

and possible influence of concomitant drugs [16]. Consid-

erable time has elapsed since this topic was examined in a

systematic fashion [6], hence our aim was to review the

available evidence on SGA-NMS, considering both pri-mary studies and case reports. In order to minimize the risk

of bias in the interpretation of available evidence, a stan-

dardized approach was used to analyze the available

information.

2 Methods

2.1 Search Strategy

The Pubmed database was searched using the followingsearch string:\Malignant AND (‘Antipsychotic Agents’

[Mesh] OR amisulpride OR aripiprazole OR asenapine OR

clozapine OR olanzapine OR paliperidone OR quetiapine

OR risperidone OR ziprasidone OR iloperidone OR zote-

pine OR sertindole OR lurasidone)[. Two independent

researchers screened and systematically assessed all

retrieved references to identify (1) primary studies on

SGA-NMS, i.e. those conducted on clinical samples; and

(3) case reports or case reviews of SGA-NMS. All works

published prior to November 2013 as well as relevant

citations obtained from bibliographies were screened. In

addition to citations in English, those written in Italian,Spanish, and French were included as two researchers were

fluent in these languages.

2.2 Inclusion and Exclusion Criteria

For the review of primary studies, any study that reported

data on NMS developed during a treatment course with any

SGA was included. If studies were conducted on samples

where NMS was developed during treatment with both

FGAs and SGAs, only those where at least 50 % of par-

ticipants were treated with SGAs were included.

For the review of case reports, the aim was to obtain themaximum degree of clinical homogeneity; hence, cases

(a) with an unclear diagnosis of NMS, meaning that the

reporting clinician did not explicitly state this diagnosis,

irrespective of the set of diagnostic criteria that were used

[1]; (b) where an SGA was given in association with

another antipsychotic (either FGA or SGA) in the week

preceding the diagnosis of NMS; and (c) where the NMS

was apparently induced by withdrawal of an antipsychotic

[15, 17], were excluded.

46 M. Belvederi Murri et al.


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2.3 Data Extraction

For the case review, researchers extracted, coded, and

analyzed relevant data available from case reports using a

standardized method (described in detail in the Methods

section of the Online Resource). Briefly, two researchers

(AG and MB), blinded to each other, coded for each case

detailed information on subject sociodemographic andclinical features, treatment with SGAs and other psycho-

tropic drugs, NMS clinical presentation, course and man-

agement. In order to provide a description of the time

course of NMS, all available data relative to the temporal

sequence of events were extracted. An adapted version of

the Francis–Yacoub NMS Rating Scale [18] was used to

improve the homogeneity for the ratings of NMS severity.

2.4 Statistical Analysis

For all cases of SGA-NMS, a summary of descriptive data

was reported, including demographic and clinical character-istics. Furthermore, to explore the presence of potential

intraclass differences between cases of NMS prompted by

different SGAs, exploratory statistical analyses were con-

ducted comparing the demographic and clinical characteris-

tics of cases by means of the Chi-square test and analysis of

variance (ANOVA). Since description of the case reports was

not conducted in a systematic fashion, a significant amountof

missing data was expected; to provide the reader with an

estimation of the representativity of results, the percentage of

cases with missing data for each comparison is reported.

Also, Pearson’s correlation index (R) and Student’s t test

were used to test whether sociodemographic and clinical

features of NMSshowed associations with theglobal severity

of NMS (expressed as the total severity score for each case).

Statistical analyses were conducted including only the SGA-

NMS groups where a sufficient number of NMS cases were

available (setting an arbitrary threshold of ten cases per

subgroup), using the Statistical Package for Social Sciences,

version 15.0 (SPSS Inc., Chicago, IL, USA).

3 Results

3.1 Search Results

The search yielded 918 citations (see Fig. S1 in the Online

Resource). Of these, six primary studies were included in

the review [11, 14, 19–22], while 247 case reports were

potentially eligible for inclusion. After full-text review,

105 more citations were excluded, leading to the inclusion

of 142 citations (case reports or case series). These

accounted for 186 individual case reports of SGA-NMS.

References for included case reports are included in the

References section of the Online Resource. Table 1 reports

the description of the included primary studies.

3.2 Case Report Analysis

Tables 2, 3 and 4 report data on cases of SGA-NMS that

were considered for statistical analysis (n = 155): 42 cases

of NMS were induced by olanzapine (OLA, mean dose12 ± 5.8 mg), 44 by risperidone (RSP, mean dose

3.7 ± 3.2 mg), 19 by quetiapine (QUE, 335 ± 270 mg),

36 by clozapine (CLZ, 332 ± 263 mg), and 14 by aripip-

razole (ARP, 18.9 ± 9.2 mg). Table 5 reports descriptive

data of those cases of SGA-NMS for which only descrip-

tive analyses are provided. These were induced by ami-

sulpride (AMI, n = 7; mean dose 480 ± 179 mg),

ziprasidone (ZPR, n = 6; 86.7 ± 46.8 mg), paliperidone

(PAL, n = 4; 7.5 ± 1.7 mg), and zotepine (ZOT, n = 4;

325 ± 247 mg). Lastly, because of a low number of cases,

ten cases of NMS induced by other antipsychotics (pero-

spirone, clotiapine, tiapride, iloperidone, asenapine, rem-oxipride) were excluded from the review.

The majority of case reports did not specify which

diagnostic criteria set was used for the diagnosis of NMS

(n = 131, 70.1 %), whereas in the remainder of cases the

Diagnostic and Statistical Manual of Mental Disorders, 4th

edition, text revision (DSM-IV-TR) criteria were used most

commonly (n = 35,18.7 %) [23], followed by the criteria

of Levenson (n = 13, 7 %) [24], Sachdev (n = 3, 1.6 %)

[25], Pope et al. (n = 2, 1.1 %) [26], and Caroff and Mann

(n = 2, 1.1 %) [27].

3.3 Intraclass Comparison of Cases of Second-

Generation Antipsychotic-Induced Neuroleptic

Malignant Syndrome (SGA-NMS)

3.3.1 Sociodemographic, Clinical Features and Treatment

with SGAs

Table 1 reports the comparison of subjects’ sociodemo-

graphic and clinical features by each SGA-NMS. In the

overall sample, the mean age was 41.5 ± 20.2. The

majority were males (62.6 %), and the diagnoses were

psychotic disorders (58.3 %), mood disorders (23.2 %),

dementia (9.3 %), or other disorders (9.3 %). Half of the

subjects receiving CLZ (50 %) and one-third of those

treated with olanzapine (34.8 %) had already suffered from

NMS in the past, whereas none of the subjects in the ari-

piprazole group ( p = 0.04) had developed NMS.

Among those patients receiving risperidone and aripip-

razole, more were antipsychotic-naı̈ve than in the clozapine

subgroup (41.2 and 38.5 vs. 4.0 %; p = 0.01). The mean

reported doses of SGAs on the day of NMS insurgence

were very similar between the five subgroups ( p = 0.89).

Second-Generation Antipsychotics and NMS 47


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T a b l e 1

S t u d i e s o n n e u r o l e p t i c m a

l i g n a n t s y n d r o m e i n d u c e d b y s e c o n d - g e n e r a t i o n a n t i p s y c h o t i c s

R e f e r e n c e s

S a m p l e

S t u d y d e s i g n a n d d a t a s o u r c e s

T r e a t m e n t

N M S c r i t e r i a ;

n o . o f c a s e s a n d

e s t i m a t e o f

i n c i d e n c e

D e a t h s

[ n ( % ) ]

M a i n fi n d

i n g s a n d l i m i t a t i o n s

B i s w a s l

e t a l .

[ 1 4 ]

1 C a s e o f N M S ; 8 , 8 5 8 s u b j e c t s ;

3 8 % F ; m e a n a g e 4

3 ±

1 7

y e a r s ; w i t h S C Z , 3 9

% ; P S Y ,

1 3 % ; o t h e r s 1 1 % ;

N S 3 3 %

O b s e r v a t i o n a l c o h o r t s t u d y .

D a t a

o n o l a n z a p i n e p r e s c r i p t i o n

s

o b t a i n e d f r o m t h e N H S d a t a b a s e

t h r o u g h p r e s c r i p t i o n - e v e n t

m o n i t o r i n g m e t h o d o v e r a

p e r i o d

o f 2 y e a r s . D a t a o n A E s

c o l l e c t e d t h r o u g h q u e s t i o n

n a i r e s

s e n t t o t h e G P s t r e a t i n g t h

e

s u b j e c t s

O L A ( 1 0 0 % )

N S ; 1 / 8 . 8 5 8

( 0 . 0 5 6 /

1 , 0 0 0 9

y e a r )

N o n e

O n l y o n e

c a s e o f N M S r e p o r t e d ,

n o t l e t h a l . E P S r e p o r t e d i n 1 3

c a s e s , m

o r e o f t e n a m o n g t h o s e

a g e d 7 0

y e a r s a n d o l d e r t h a n i n

y o u n g e r s u b j e c t s

C h e n e t a l .

[ 1 9 ]

5 0 S u b j e c t s w i t h N M S ; 4 4 % F ;

m e a n a g e 4 1 ±

1 4 y e a r s ; w i t h

B D , 1 0 0 % . 8 0 0 c o n

t r o l s w i t h o u t

N M S m a t c h e d f o r d i a g n o s i s , a g e ,

a n d d a t e o f B D i n s u

r g e n c e

C a s e – c o n t r o l s t u d y . D a t a f r o m

m e d i c a l c l a i m s d a t a b a s e o

v e r a

5 - y e a r p e r i o d . C a s e s w i t h

N M S

i d e n t i fi e d f r o m 1 5 4 , 4 7 4 s u

b j e c t s

w i t h B D , t h r o u g h s p o n t a n e o u s

r e p o r t s b y t r e a t i n g p h y s i c i a n s .

C a s e s : A P 3 4 % , o f w h i c h

7 2 % w e r e S G A s ( O L A ,

1 8 % ; Q U E , 2 8 % ; R S P :

1 2 % ; Z P R : 1 2 % ; C L Z :

2 % ) ; F G A s : 8 % ; L I T :

1 0 % ; B D Z : 1 6 % ; A P K :

8 % ; A D : 3 0 %

I C D - 9 ;

5 0 / 1 5 4 . 4 7 4

( 0 . 0 6 4 /

1 0 0 0 * y e a r ) )

N o n e

N M S w a s a s s o c i a t e d w i t h t h e u s e

o f A P ( a O R 2 . 4 ) , m a l e g e n d e r

( a O R 2 . 1 ) , c o n f u s i o n ( a O R 2 . 9 ) ,

d e h y d r a

t i o n ( a O R 4 . 0 ) , d e l i r i u m

( a O R 4 . 9 ) , a n d E P S ( a O R 3 . 5 ) .

N o t a b l y

, o n l y 3 4 % o f N M S

c a s e s h a d b e e n c l a s s i fi e d a s

c u r r e n t l y r e c e i v i n g A P ; a u t h o r s

c o m m e n t e d t h a t m o s t A P

t r e a t m e n t l i k e l y h a d n o t b e e n

r e g i s t e r e d ( p a i d o u t - o f - p o c k e t b y

p a t i e n t s )

N a k a m u r a

e t a l .

[ 2 0 ]

2 1 0 C a s e s w i t h S G A - N M S ; I N P T ,

1 0 0 % ; 4 2 % F ; w i t h p s y c h i a t r i c

d i a g n o s e s a n d n e u r o

l o g i c a l

d i a g n o s e s ; 2 1 0 c o n t r o l s w i t h

F G A - N M S m a t c h e d

b y A P

e x p o s u r e

C a s e – c o n t r o l s t u d y . D a t a f r o m

a d m i n i s t r a t i v e c l a i m s d a t a

b a s e

( J a p a n e s e D i a g n o s i s P r o c e

d u r e

C o m b i n a t i o n ) r e g i s t e r i n g

a d m i s s i o n s t o g e n e r a l h o s p i - t a l s

o v e r a p e r i o d o f 4 y e a r s

( n = 1 2 m i l l i o n ) . C a s e s a n d

c o n t r o l s w e r e s e l e c t e d f r o m

1 , 5 8 5 a d m i s s i o n s f o r N M S

C a s e s : S G A s , 1 0 0 %

C o n t r o l s : F G A s , 1 0 0 %

I C D - 1 0 ; N A

S G A s : 7

( 3 . 3 )

F G A s : 1 6

( 7 . 6 )

C o m p a r e d w i t h F G A - N M S , S G A -

N M S w e r e a s s o c i a t e d w i t h f e w e r

a d m i s s i o n s t o I C U ( 2 1 v s . 3 1 % ;

p = 0 . 0 2 ) a n d w i t h l o w e r

m o r t a l i t y ( a O R 0 , 4 4 ; p = 0 . 0 8 )

a f t e r a d j u s t i n g f o r g e n d e r , a g e ,

a n d C V

D

C V D w a s a s s o c i a t e d w i t h

i n c r e a s e

d N M S - r e l a t e d m o r t a l i t y



5/18

T a b l e 1

c o n t i n u e d

R e f e r e n c e s

S a m p l e


T r e a t m e n t



e s t i m a t e o f

i n c i d e n c e

D e a t h s

[ n ( % ) ]

M a i n fi n d


N i e l s e n

e t a l .

[ 2 1 ]


m e a n a g e 5 1 y e a r s ;

w i t h P S Y ,

4 8 % ; O R G , 3 1 % ;

M D , 1 6 % ;

N E U R , 5 %

4 1 5 C o n t r o l s m a t c h e d

b y s e x , a g e ,

a n d d i a g n o s i s ; P S Y ,

4 8 % ; O R G ,

3 1 % ; M D , 1 6 % ; N

E U R , 5 %

R e t r o s p e c t i v e a n d c a s e – c o n t r o l

s t u d y . D a t a f r o m t h e D P C

R R

o v e r a p e r i o d o f 1 2 y e a r s

( 2 2 4 , 0 0 0 s u b j e c t s )

C a s e s a n d c o n t r o l s w e r e f o l l o w e d

f o r 3 m o n t h s b e f o r e a n d a

f t e r

N M S d i a g n o s i s

C a s e s : S G A s , 3 7 % ; F G A s ,

6 9 % ( h i g h p o t e n c y , 1 7 % ;

m e d i u m p o t e n c y , 2 3 % ; l o w

p o t e n c y , 2 8 % ; d e p o t , 1 3 % ) ;

B D Z , 6 5 % ; L I T , 1 2 %

C o n t r o l s : S G A s , 1 9 % ; F G A s ,

2 7 % ( h i g h p o t e n c y , 4 % ;

m e d i u m p o t e n c y , 1 0 % ; l o w

p o t e n c y , 1 3 % ; d e p o t , 6 % ) ;

B D Z , 3 2 % ; L I T , 4 %

I C D - 1 0 ;

8 3 / 2 2 4 . 3 7 2

( 0 . 0 3 1 /

1 0 0 0 * y e a r )

7 ( 8 . 4 )

I n t h e g e n

e r a l s a m p l e ( n = 8 3 ) , t h e

r i s k o f d e v e l o p i n g N M S w a s

h i g h e r w i t h l i t h i u m u s e ( a O R

5 . 9 ; p \

0 . 0 5 ) , d e p o t ( a O R 5 . 7 ;

p = 0 . 0 0 5 ) , S G A s ( a O R 3 . 0 ; p \

0 . 0 1 ) , b

e n z o d i a z e p i n e u s e ( a O R

2 . 7 ; p \

0 . 0 0 5 ) , a n d d o s e o f A P

( a O R 1 . 0 0 2 ; p \

0 . 0 5 )

I n t h e g r o

u p o f p a t i e n t s t r e a t e d

w i t h A P

f o r 3 m o n t h s b e f o r e

h o s p i t a l i z a t i o n ( n = 6 2 ) , t h e r i s k

o f d e v e l o p i n g N M S w a s h i g h e r

w i t h h i g h - p o t e n c y F G A s ( a O R

2 3 . 4 ; p \

0 . 0 0 1 ) , S G A s ( a O R

4 . 7 ; p =

0 . 0 0 1 ) , a n d d e p o t A P

( a O R 4 . 5 ; p \

0 . 0 0 5 )

M o r t a l i t y

w i t h i n t h e fi r s t 3 0 d a y s

a f t e r N M S w a s h i g h e r a m o n g

c a s e s ( H

R 1 . 9 ; p \

0 . 0 1 ) ,

e s p e c i a l l y f e m a l e s . C a s e s a n d

c o n t r o l s

w e r e n o t m a t c h e d b y A P

u s e , b u t f o r s e x , a g e , a n d

d i a g n o s i s

T r o l l o r

e t a l .

[ 1 1 ]

1 6 5 S u b j e c t s w i t h S G

A - N M S ;

2 7 % F ; m e a n a g e 4 9 y e a r s ; w i t h

P S Y , 4 9 % ; O R G , 2

% ; M D ,

3 % ; A N X , 1 % ; N S , 4 6 % . 4 3

c o n t r o l s w i t h F G A - N M S ; 3 0 %

F ; m e a n a g e 6 2 y e a r s ; w i t h P S Y ,

3 0 % ; M D , 7 % ; O R G , 2 % ;

o t h e r , 9 % ; N S , 5 1 %

R e t r o s p e c t i v e s t u d y . D a t a f r o m

s p o n t a n e o u s N M S r e p o r t i n g i n

A u s t r a l i a n A D R A C d a t a b a s e

o v e r a p e r i o d o f 1 6 y e a r s

S u b j e c t s i n p o l y t h e r a p y w e r e

e x c l u d e d ( n = 8 5 )

S G A - N M S : C L Z , 3 7 % ; R S P ,

1 6 % ; O L A , 1 4 % ; Q U E ,

7 % ; A M I , 3 % ; A R P , 2 % ;

P A L , 1 %

D e l p h i

c o n s e n s u s ;

N A

S G A s : 3 % ;

F G A s :

1 6 %

M o r t a l i t y

r a t e i n i n d i v i d u a l s w i t h

S G A - N M S w a s s i g n i fi c a n t l y

l o w e r t h a n t h a t o f F G A - N M S ,

b u t t h e

d i f f e r e n c e w a s r e d u c e d

a f t e r a d j u s t i n g f o r a g e . N o o t h e r

s i g n i fi c a n t d i f f e r e n c e s w e r e

f o u n d b

e t w e e n t h e c l i n i c a l

p r e s e n t a t i o n o f S G A - N M S a n d

t h a t o f F G A - N M S , e x c e p t f o r

c l o z a p i n e - i n d u c e d N M S t h a t w a s

c h a r a c t e r i z e d b y a l o w e r

p r e s e n c e o f r i g i d i t y a n d o t h e r

E P S c o m p a r e d w i t h o t h e r S G A -

N M S



6/18

T a b l e 1

c o n t i n u e d

R e f e r e n c e s

S a m p l e


T r e a t m e n t



e s t i m a t e o f

i n c i d e n c e

D e a t h s

[ n ( % ) ]

M a i n fi n d


S u e t a l .

[ 2 2 ]


m e a n a g e 4 3 ±

1 8 y e a r s ; w i t h

P S Y , 4 6 % ; B D , 2 7

% ;

S C Z A F F , 1 2 % ; D E P , 4 % ;

o t h e r s , 1 0 % ; 2 5 4 c o n t r o l s

m a t c h e d ( 1 : 4 ) b y a g

e , g e n d e r ,

a n d d i a g n o s i s : P S Y , 4 6 % ; B D ,

2 7 % ; S C Z A F F , 1 3 ; D E P , 5 % ;

o t h e r s , 9 %

C a s e – c o n t r o l s t u d y . D a t a f r o m t h e

S o u t h L o n d o n a n d M a u d s l e y

N H S F o u n d a t i o n T r u s t C a

s e

R e g i s t e r o v e r a p e r i o d o f 9

y e a r s .

A t l e a s t o n e c r i t e r i a f o r N

M S

d i a g n o s i s . D r u g s w e r e

a d m i n i s t e r e d 5 ( o r a l A P ) o r 1 5

( d e p o t A P ) d a y s b e f o r e t h e i n d e x

d a t e

4 8 % S G A s o n l y , 1 8 % F G A s

o n l y , 4 % A R P o n l y , 4 5 %

p o l y t h e r a p y , 1 0 % d e p o t o n l y

L e v e n s o n ,

A d d o n i z i o ,

P o p e ( d e fi n i t e

o r p r o b a b l e ) ,

C a r o f f ,

A d i t y a n j e e ,

D S M - I V

D e a t h s : N A

I n u n i v a r i a t e a n a l y s e s , F G A s w e r e

a s s o c i a t e d w i t h a n O R o f N M S

o f 3 . 9 ( p \

0 . 0 0 1 ) , w h e r e a s

S G A s w

e r e n o t a s s o c i a t e d w i t h

s i g n i fi c a n t l y h i g h e r r i s k o f N M S ,

w i t h t h e e x c e p t i o n o f A R P ( O R

2 . 5 ; p =

0 . 0 4 ) . I n m u l t i v a r i a t e

a n a l y s e s , c o m p a r e d w i t h S G A s ,

t h e O R

f o r N M S w a s s i g n i fi c a n t

f o r F G A

s ( 2 . 8 1 ; p = 0 . 0 1 ) , S G A /

F G A a s

s o c i a t e d ( 5 . 5 2 ;

p \

0 . 0 0 1 ) , b u t n o t f o r A R P

( p = 2 . 4 3 ) . F l u c t u a n t d o s e s a n d

n o n - W h

i t e e t h n i c i t y w e r e a l s o

s i g n i fi c a n t r i s k f a c t o r s f o r N M S

N M S c a s e d e fi n i t i o n w a s b a s e d o n

f u l fi l l i n g a t l e a s t o n e o f t h e s i x

c r i t e r i a

s e t , r e s u l t i n g i n a h i g h

d e g r e e o f d i a g n o s t i c

h e t e r o g e n e i t y . O n l y o n e c a s e

f u l fi l l e d

a l l s i x c r i t e r i a

A E s a d v e r s e e v e n t s ,

A D a n t i d e p r e s s a n t s , A D R A C A d v e r s e D r u g R e a c t i o n A d v i s o r y C o m m i t e e ,

A M I a m i s u l p r i d e , A N X A

n x i e t y D i s o r d e r s , a O R a d j u s t e d o d d s r a t i o

, A P a n t i p s y c h o t i c , A P K

a n t i p a r k i n s o n a g e n t s ,

A R P a r i p i p r a z

o l e , B D b i p o l a r d i s o r d e r ,

B D Z b e n z o d i a z e p i n e s ,

C L Z c l o z a p i n e , C V D c a r d i o v a s c u l a r d i s e a s e ,

D E P u n i p o l a r d e p r e s s i o n ,

D P C R R D

a n i s h P s y c h i a t r i c C e n t r a l

R e s e a r c h R e g i s t e r , D S M - I V D i a g n o s t i c a n d S t a t i s t i c a l M a n u a l o f M e n t a l D i s o r d e r s , 4 t h e d i t i o n , E P S e x t r a p y r a m i d a l s y m p t o m s , F f e m a l e , F G A fi r s t - g e n e r a t i o n a n t i p s y c h o t i c , F G A - N M S F G A -

i n d u c e d N M S ,

G P s g e n e r a l p r a c t i t i o n e r s ,

H R h a z a r d r a t i o , I C D - 9 I n t e r n a t i o n a l C l a s s i fi c a t i o n o f D i s e a s e s , 9 t h r e v i s i o n ,

I C D - 1 0 I n t e r n a t i o n a l C l a s s i fi c a t i o n o f D i s e a s e s , 1 0 t h r e v i s i o n ,

I C U

i n t e n s i v e c a r e u n i t ,

I N P T i n p a t i e n t s ,

L I T l i t h i u m ,

M D m o o d d i s o r d e r ,

N A n o t a p

p l i c a b l e , N E U R n e u r o t i c d i s o r d e r s , N

H S N a t i o n a l H e a l t h S e r v i c e , N

M S n e u r o l e p t i c m a l i g n a n t s y n d r o m e , N S n o t

s p e c i fi e d ,

O L A o l a n z a p i n e ,

O R o d d s r a t i o , O R G o r g a n i c d i s o r d e r s , P A L p a l i p e r i d o n e ,

P S Y p s y c h o t i c d i s o r d e r s , Q U E q

u e t i a p i n e , R S P r i s p e r i d o n e ,

S C Z A F F s c h i z

o a f f e c t i v e d i s o r d e r ,

S C Z

s c h i z o p h r e n i a , S G A s e c o n d - g e n e r a t i o n a n t i p s y c h o t i c , S G A - N M S S G A - i n d u c e d

N M S ,

Z P R z i p r a s i d o n e



7/18

Instead, a steep dose titration before NMS was found morefrequently in the aripiprazole group than in the quetiapine

group (50 vs. 10.5 %; p = 0.04). Olanzapine, quetiapine,

and risperidone were more often associated with antide-

pressant use than clozapine and aripiprazole. Lithium was

prescribed to 5.3 % of participants using quetiapine and up

to 13.9 % of those taking clozapine.

3.3.2 NMS Clinical Features

The comparisons of the prevalence, duration, and

severity of NMS symptoms are reported in Table 3. The

clinical presentation of NMS showed significant differ-ences according to the SGA used; rigidity and tremor

were less frequent in CLZ-NMS than in other subgroups

( p\ 0.01 and p = 0.03, respectively). While a degree of

hyperpyrexia was almost ubiquitary, higher temperatures

were less commonly observed for aripiprazole (58.3 %)

than other SGAs, but this difference did not reach sta-

tistical significance ( p = 0.10). Diaphoresis was constant

or very frequent in olanzapine, quetiapine, and clozapine

(100, 100, and 94 %, respectively), less frequent in

risperidone (75 %), and in cases of aripiprazole-inducedNMS (ARP-NMS) [42.9 %; p = 0.001]. Considering

laboratory tests, both CK elevation and leukocyto-

sis were very frequent without showing intra-class

differences.

Global severity was significantly lower for CLZ–NMS

than risperidone-induced NMS (RSP-NMS) [ p = 0.02] or

olanzapine-induced NMS (OLA-NMS) [ p = 0.03]. There

was no significant association between global severity and

age (r = 0.07, p = 0.48), gender (t = 1.37, p = 0.17),

diagnoses (F = 0.18, p = 0.91), antipsychotic dose

(r = 0.08, p = 0.44) or percentage of dose increase in the

preceding week (r = 0.13, p = 0.48), use of mood stabi-lizers (t = 0.49, p = 0.69) or benzodiazepines (t = 0.76,

p = 0.45) in the preceding week. There was a statistical

trend for an association between antidepressant use in the

past week and a higher global severity (37.0 ± 9.6 vs.

32.4 ± 8.7; p = 0.08) but this disappeared after adjusting

for the type of antipsychotic.

There were differences in the timing of the onset of

some symptoms between the SGA-NMS subgroups (see

Table 5), although no comparison reached statistical

Table 2 Cases of neuroleptic malignant syndrome induced by olanzapine, quetiapine, risperidone, aripiprazole, and clozapine

OLA

(n = 42)

QUE

(n = 19)

RSP

(n = 44)

ARP

(n = 14)

CLZ

(n = 36)

Missing

[n (%)]

Statistics

Gender [female; %] 33.3 42.1 50 42.9 22.2 – v2 = 7.18, df = 4, p = 0.13

Age [years; mean ± SD] 46.2 ± 22.4 45.3 ± 18.8 39.6 ± 21.2 32.1 ± 18.2 39.9 ± 16.3 – F = 1.68, df = 4, p = 0.16

Ethnicity [Caucasian; %] 41.2 42.9 55 60 87.5 93 (60) v2 = 9.74, df = 12, p = 0.64c

Diagnosis [%] 4 (2.6) v2

= 13.99, df = 12, p = 0.3Psychotic disorders 52.5 44.4 50 71.4 77.1

Mood disorders 25 27.8 25 21.4 17.1

Dementia 15 15 9.1 – 2.9

Other 7.5 7.5 15.9 7.1 2.9

Previous NMS [%] 34.8 12.5 12.5 0 50 119 (76) v2 = 9.74, df = 4, p = 0.04*c

AP naive [%] 26.7 15.4 41.2 38.5 4.0 40 (26) v2 = 12.15, df = 4, p = 0.02*,c

Dose [mg; mean ± SD] 12.1 ± 5.9 335 ± 270 3.7 ± 3.2 18.9 ± 9.2 332 ± 263 23 (15) –

CPZ eq [mean ± SD] 253 ± 124 236 ± 190 279 ± 240 295 ± 144 308 ± 243 23 (15) F = 0.48, df = 4, p = 0.75

Dose increase [%]a 33.3 15.8 25 50 36.1 – v2 = 5.71, df = 4, p = 0.22

Dose increase C50 [%]b 30.0 10.5 25 50 33.3 – v2 = 6.87, df = 4, p = 0.14

Other treatments [%]

SSRI 11.9 10.5 11.4 7.1 2.8 31 (20) v2 = 2.54, df = 4, p = 0.64

Other AD 4.8 5.3 6.8 0 2.8 31 (20) v2 = 1.49, df = 4, p = 0.83

LIT 11.9 5.3 13.6 7.1 13.9 31 (20) v2 = 1.38, df = 4, p = 0.85

Other MS 21.4 10.5 13.6 7.1 8.3 31 (20) v2 = 3.7, df = 4, p = 0.45

AD antidepressant, AP antipsychotic, ARP aripiprazole, CLZ clozapine, CPZ eq chlorpromazine equivalents, df degrees of freedom, LIT lithium,

NMS neuroleptic malignant syndrome, OLA olanzapine, QUE quetiapine, RSP risperidone, SSRI selective serotonin reuptake inhibitor, MS mood

stabilizers, SD standard deviation

* p\ 0.05a Any dose increase of AP in the 5 days preceding NMS onsetb Percentage of dose increase was calculated as 100 % when the APs were newly introduced in the 5 days before NMS diagnosisc Missing values over 25 %



8/18

T a b l e 3

C l i n i c a l f e a t u r e s o f n e u r o l e p t i c m a l i g n a n t s y n d r o m e i n d u c e d b y o l a n

z a p i n e , q u e t i a p i n e , r i s p e r i d o n e , a r i p i p r a z o l e , a n d c l o z a p i n e

O L A ( n = 4 2 )

Q U E ( n = 1 9 )

R S P ( n = 4 4 )

A R P ( n = 1 4 )

C L Z

( n = 3 6 )

M i s s i n g [ n ( % ) ]

S t a t i s t i c s

S y m p t o m s [ % ]

M e n t a l s t a t u s c h a n g e

1 0 0

8 5 . 7

8 8 . 2

1 0 0

9 6 . 6

3 3 ( 2 1 )

v 2

=

7 . 1 9 5 ,

d f =

4 , p = 0 . 1 3

R i g i d i t y

9 1 . 4

9 2 . 3

9 4 . 1

1 0 0

6 7 . 6

2 7 ( 1 7 )

v 2

=

1 5 . 4 7 2 ,

d f =

4 , p \

0 . 0 1 *

T r e m o r

9 2 . 3

1 0 0

9 1 . 7

8 1 . 8

4 4 . 4

1 0 7 ( 6 9 )

v 2

=

1 0 . 5 9 6 ,

d f =

4 , p = 0 . 0 3 * d

O t h e r E P S

8 4 . 6

7 1 . 4

6 6 . 7

8 3 . 3

5 8 . 3

1 0 5 ( 6 8 )

v 2

=

2 . 6 9 1 ,

d f =

4 , p = 0 . 6 1 d

H y p e r p y r e x i a

8 8 . 9

9 2 . 3

9 7 . 3

8 4 . 6

9 1 . 4

2 1 ( 1 4 )

v 2

=

2 . 7 9 , d f =

4 , p = 0 . 5 9

T e m p e r a t u r e C 3 8 C

7 9 . 4

7 8 . 9

9 4 . 3

5 8 . 3

7 9 . 2

3 1 ( 2 0 )

v 2

=

1 3 . 3 8 6 ,

d f =

8 , p = 0 . 1 0

D i a p h o r e s i s

1 0 0

1 0 0

7 5

4 2 . 9

9 5

9 0 ( 5 8 )

v 2

=

1 9 . 4 6 7 ,

d f =

4 , p = 0 . 0 0 1 * d

B P a l t e r a t i o n

8 8 . 2

9 0

7 3 . 7

7 6 . 9

8 1

5 8 ( 3 7 )

v 2

=

2 . 4 9 9 ,

d f =

4 , p = 0 . 6 4 d

T a c h y c a r d i a

1 0 0

1 0 0

9 5 . 7

9 1 . 7

1 0 0

4 5 ( 2 9 )

v 2

=

5 . 0 6 7 ,

d f =

4 , p = 0 . 2 8 d

T a c h y p n e a

7 0

1 0 0

7 0

6 0

1 0 0

1 1 3 ( 7 3 )

v 2

=

5 . 1 6 3 ,

d f =

4 , p = 0 . 2 7 d

D y s p h a g i a

1 3 . 2

8 . 7

1 7 . 6

1 5 . 4

1 1 . 1

5 1 ( 2 7 )

v 2

=

1 . 1 3 9 ,

d f =

4 , p = 0 . 8 9 d

O t h e r a u t o n o m i c s y m p t o m s

1 4 . 3

1 5 . 8

2 5

3 5 . 7

2 5

–

v 2

=

3 . 8 4 5 ,

d f =

4 , p = 0 . 4 3

L a b o r a t o r y t e s t s

C K e l e v a t i o n [ % ]

9 7 . 4

9 1 . 7

9 7 . 1

9 2 . 3

8 5 . 2

1 8 ( 1 1 )

v 2

=

4 . 8 8 5 ,

d f =

4 , p = 0 . 3 0

C K [ 1 0 0 U I / l ; m e a n ±

S D ]

2 2 . 8 ±

5 5 . 0

2 9 . 1 ±

4 7 . 8

5 7 . 3 ±

1 5 . 5

2 4 . 8 ±

6 3 . 6

1 1 . 2

±

4 1 . 9

3 3 ( 2 1 )

F =

1 . 3 4

7 , d f =

4 , p = 0 . 3 3

C K p e a k [ 1 0 0 U I / l ; m e a n ±

S D ]

4 8 . 1 ±

6 5 . 5

5 4 . 8 ±

5 7 . 1

8 5 . 0 ±

1 7 8 . 9

3 5 . 9 ±

6 5 . 6

5 4 . 6

±

1 2 1 . 7

3 3 ( 2 1 )

F =

0 . 5 6

9 , d f =

4 , p = 0 . 6 9

L e u k o c y t o s i s [ % ] a

8 0 . 0

8 0

7 0 . 8

7 0 . 0

7 5

5 4 ( 3 5 )

v 2

=

0 . 8 2 4 ,

d f =

4 , p = 0 . 9 4 d

W B C [ 1 , 0 0 0 U / l ; m e a n ±

S D ]

1 4 . 3 ±

7 . 6

1 1 . 9 ±

4 . 8

1 5 . 3 ±

5 . 2

1 5 . 5 ±

5 . 4

1 3 . 9

±

6 . 0

7 8 ( 5 0 )

F =

0 . 4 4

3 , d f =

4 , p = 0 . 7 8 d

S y m p t o m d u r a t i o n [ d a y s ; m e a n ±

S D ]

8 ±

5 . 4

1 3 . 7 ±

8 . 4

9 . 7 ±

9 . 8

7 . 5 ±

3 . 0

1 0 . 4

±

9 . 9

6 5 ( 4 2 )

F =

1 . 1 7

4 , d f =

4 , p = 0 . 3 3 d

N M S s e v e r i t y [ p o i n t s ; m e a n ±

S D ] b

3 5 . 3 ±

8 . 3

3 1 . 1 ±

8

3 6 . 3 ±

8 . 3

3 1 . 6 ±

1 0 . 1

2 8 . 8

±

8 . 3

5 7 ( 3 6 )

F =

3 . 3 ,

d f =

4 , p = 0 . 0 1 * d

T i m i n g o f N M S s y m p t o m s c

M e n t a l s t a t u s c h a n g e

1 . 0

0 . 5

1 . 5

0 . 8

1 . 0

5 7 ( 3 6 )

F =

0 . 3 1

9 , d f =

4 , p = 0 . 8 6 d

R i g i d i t y

1 . 2

0 . 3

1 . 5

1 . 1

- 1 . 2

4 8 ( 3 0 )

F =

1 . 1 6

3 , d f =

4 , p = 0 . 3 3 d

T r e m o r

1

0 . 7

1 . 7

1 . 1

0 . 0

1 1 5 ( 7 4 )

F =

0 . 1 8

3 , d f =

4 , p = 0 . 9 4 d

O t h e r E P S

1 . 9

0 . 3

3 . 4

1 . 6

2 . 0

–

F =

0 . 0 4

0 , d f =

4 , p = 0 . 9 9

D i a p h o r e s i s

0 . 7

0 . 8

- 0 . 1

0 . 0

1 . 4

1 0 3 ( 6 6 )

F =

0 . 2 1

2 , d f =

4 , p = 0 . 9 3 d

H y p e r p y r e x i a

0 . 7

0 . 1

0 . 7

- 2 . 2

2 . 2

4 3 ( 2 7 )

F =

1 . 3 6

3 , d f =

4 , p = 0 . 2 5 d

T a c h y c a r d i a

- 0 . 4

0 . 3

- 0 . 2

- 3 . 3

1 . 4

6 1 ( 3 9 )

F =

1 . 9 9

2 , d f =

4 , p = 0 . 1 0 d

T a c h y p n e a

- 1 . 1

0 . 2

- 0 . 5

0 . 0

- 0 . 5

1 1 3 ( 7 2 )

F =

0 . 3 7

3 , d f =

4 , p = 0 . 8 3 d

B P a l t e r a t i o n

- 0 . 1

0 . 1

- 0 . 1

0 . 2

0 . 4

7 4 ( 4 7 )

F =

0 . 2 8

2 , d f =

4 , p = 0 . 8 9 d

O t h e r a u t o n o m i c d i s o r d e r s

5 . 3

0 . 0

2 . 7

0 . 0

3 . 0

–

F =

0 . 5 3

9 , d f =

4 , p = 0 . 7 1

C K

- 0 . 7

0 . 0

0 . 0

- 3 . 6

- 0 . 4

4 2 ( 2 7 )

F =

1 . 9

second-generation antipsychotics and neuroleptic malignant

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